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Antimicrobial Agents and Chemotherapy, January 2009, p. 112-122, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.01162-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans: Implications for Interpretive Breakpoints{triangledown}

Guillermo Garcia-Effron, Steven Park, and David S. Perlin*

Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103

Received 29 August 2008/ Returned for modification 17 September 2008/ Accepted 16 October 2008

A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-β-D-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and Ki increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter Km values, although some mutations decreased the Vmax. Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-β-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of ≥2 µg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of ≤50-fold for the Ki was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of ≥0.5 µg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of ≥2 µg/ml for the three echinocandin drugs. The 1,3-β-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (≤0.5 µg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.

* Corresponding author. Mailing address: Public Health Research Institute, New Jersey Medical School-UMDNJ, 225 Warren Street, Newark, NJ 07103. Phone: (973) 854-3200. Fax: (973) 854-3101. E-mail: perlinds{at}umdnj.edu

{triangledown} Published ahead of print on 27 October 2008.

Antimicrobial Agents and Chemotherapy, January 2009, p. 112-122, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.01162-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Garcia-Effron, G., Lee, S., Park, S., Cleary, J. D., Perlin, D. S. (2009). Effect of Candida glabrata FKS1 and FKS2 Mutations on Echinocandin Sensitivity and Kinetics of 1,3-{beta}-D-Glucan Synthase: Implication for the Existing Susceptibility Breakpoint. Antimicrob. Agents Chemother. 53: 3690-3699 [Abstract] [Full Text]  
  • Arendrup, M. C., Garcia-Effron, G., Buzina, W., Mortensen, K. L., Reiter, N., Lundin, C., Jensen, H. E., Lass-Florl, C., Perlin, D. S., Bruun, B. (2009). Breakthrough Aspergillus fumigatus and Candida albicans Double Infection during Caspofungin Treatment: Laboratory Characteristics and Implication for Susceptibility Testing. Antimicrob. Agents Chemother. 53: 1185-1193 [Abstract] [Full Text]  


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